Hydroxy-, alkoxy- and benzyloxy-substituted phospholipids

ABSTRACT

Novel hydroxy-, alkoxy- and benzyloxy-substituted phospholipids, a process for the preparation thereof, and methods for treating pain, phospholipase, A 2  mediated inflammation and similar conditions utilizing compounds or compositions thereof are disclosed.

This application is a continuation-in-part of U.S. application Ser. No.076,966 filed Jul. 23, 1987, now abandoned.

This invention relates to hydroxy-, alkoxy- and benzyloxy-substitutedphospholipids. More particularly, this invention relates toalkylphospholipids of the formula: ##STR1## wherein R¹ is selected fromthe group consisting of hydrogen, substituted and unsubstituted phenylradicals, and substituted and unsubstituted phenoxy radicals; R² isselected from the group consisting of hydrogen, alkyl radicals having upto 6 carbon atoms, inclusive, and phenyl-substituted andphenyl-unsubstituted benzyl radicals; R³ is ##STR2## wherein R⁴ is analkyl radical having up to 6 carbon atoms, inclusive; R⁵ and R⁶ areindependently alkyl radicals having up to 6 carbon atoms, inclusive, or,taken together with the nitrogen atom to which they are attached form agroup of the formula ##STR3## wherein r is 0 or 1; s is an integerwhich, depending upon the valency of W, has a value from 0 to 2inclusive; and W is selected from the group consisting of carbon,oxygen, nitrogen and sulfur atoms, with the proviso that when W is otherthan a carbon atom, r is 1; A is a divalent radical of the formula--C_(n) H_(2n) -- wherein n is an integer having a value from 1 to 20,inclusive; m is an integer having a value of 3 or 4; A¹ is a bivalentradical of the formula --C_(p) H_(2p) -- wherein p is an integer havinga value from 2 to 10, inclusive with the proviso that the sum of n and pdoes not exceed 25; the geometrical isomers, or optical antipodesthereof, which are useful as antiinflammatory agents alone or incombination with one or more adjuvants.

Preferred alkylphospolipids of this invention are compounds of theformula: ##STR4## wherein R¹ is selected from the group consisting ofhydrogen, substituted and unsubstituted phenyl radicals, and substitutedand unsubstituted phenoxy radicals; R² is selected from the groupconsisting of hydrogen alkyl radicals having up to 6 carbon atomsinclusive, and phenyl-substituted and phenyl-unsubstituted benzylradicals; R⁴ is an alkyl radical having up to 6 carbon atoms, inclusive;R⁵ and R⁶ are independently alkyl radicals having up to 6 carbon atoms,inclusive, or taken together with the nitrogen atom to which they areattached form a group of the formula ##STR5## wherein r is 0 or 1; s isan integer which, depending upon the valency of W, has a value of from 0to 2 inclusive; W is selected from the group consisting of carbon,oxygen, nitrogen and sulfur atoms, with the proviso that when W is otherthan a carbon atom, r is 1; x is an integer having a value from 1 to 20inclusive; and y is an integer having a value from 2 to 5 inclusive; thegeometrical isomers or optical antipodes thereof.

Subgeneric to the phospolipids of this invention are compounds wherein:

(a) R¹ is hydrogen;

(b) R¹ is a group of the formula ##STR6## wherein a is an integer havinga value from 0 to 2, inclusive, X is selected from the group consistingof alkyl radicals having 1 to 6, preferably 1 to 3, carbon atoms,inclusive; alkoxy radicals having 1 to 6, preferably 1 to 3, carbonatoms, inclusive; and halogen, preferably fluorine or chlorine, hydroxy,and trifluoromethyl radicals; wherein for each value of a, X may be thesame or different;

(c) R¹ is a group of the formula ##STR7## wherein b is an integer havinga value from 0 to 2, inclusive, and Y is selected from the groupconsisting of alkyl radicals having 1 to 6, preferably 1 to 3 carbonatoms, inclusive; alkoxy radicals having 1 to 6, preferably 1 to 3carbon atoms, inclusive, and halogen, preferably fluorine or chlorine,hydroxy, and trifluoromethyl radicals; wherein for each value of b, Ymay be the same or different;

(d) R² is hydrogen;

(e) R² is an alkyl radical having up to 6 carbon atoms inclusive;

(f) R² is ##STR8## wherein c is an integer having a value of 0 or 1, andZ is an alkoxy radical having 1 to 6, preferably 1 to 3, carbon atoms,inclusive;

(g) R³ is ##STR9## wherein R⁴, R⁵ and R⁶ are independently alkylradicals having up to 6 carbon atoms, inclusive;

(h) R³ is ##STR10## wherein R⁴ is an alkyl radical having up to 6 carbonatoms inclusive, and R⁵ and R⁶ together with the nitrogen atom to whichthey are attached form a group of the formula ##STR11## wherein W isselected from the group consisting of carbon, oxygen, sulfur andnitrogen atoms; s is an integer which, depending upon the valency of W,has a value from 0 to 2 inclusive; and r is 0 or 1.

(i) A is --C_(n) H_(2n) -- wherein n is an integer having a value from 1to 20, inclusive, preferably from 7 to 17, inclusive; and

(j) A is --(CH₂)_(x) -- wherein x is an integer having a value from 1 to20, inclusive, preferably from 7 to 17, inclusive;

(k) A¹ is --C_(p) H_(2p) -- wherein p is an integer having a value from2 to 10, inclusive, preferably 2 to 5, most preferably 2;

(l) A¹ is --(CH₂)_(y) -- wherein y is an integer having a value from 2to 5, inclusive.

As used herein the term "alkyl" refers to a straight or branched chainhydrocarbon radical containing no unsaturation, such as, for examplemethyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl, 2-pentyl, 3-hexyland the like; the term "alkoxy" refers to a monovalent substituent whichconsists of an alkyl group linked through an ether oxygen and having itsfree valence bond from the ether oxygen such as, for example methoxy,ethoxy, 1- and 2-propoxy, 1-butoxy, 1,2-dimethylethoxy, 1- and2-pentoxy-, 3-hexoxy- and the like; and the term "benzyloxy" refers to amonovalent substituent which consists of a benzyl group linked throughan ether oxygen and having its free valence bond from the ether oxygen;the term "halogen" refers to a member of the family of fluorine,chlorine, bromine or iodine; the term "phenoxy" refers to a monovalentsubstituent which consists of a phenyl group linked through an etheroxygen and havings its free valence bond from the ether oxygen; the term"alkanol" refers to a compound formed by a combination of an alkyl groupand a hydroxy radical such as, for example methanol, ethanol, 1- and2-propanol, t-butanol, and the like; and the term "alkanoic acid" refersto a compound formed by combination of a carbonyl group with a hydrogenatom or alkyl group such as, for example, formic acid, acetic acid,propanoic acid, 2,2-dimethylacetic acid, hexanoic acid and the like.

The hydroxy-, alkoxy- and benzyloxy-substituted phospholipids of thisinvention are synthesized by the processes illustrated in ReactionSchemes A, B, C, D and E.

As shown by Reaction Scheme A, benzyloxy- or alkoxy-substituted alkanolsof the formula ##STR12## wherein R¹ is hydrogen, are produced byreacting an aldehyde 1 with an organometallic reagent 2 to produce anhydroxy-substituted 1-alkene 3 which is hydrated to an alkan-1-ol 5 viathe corresponding alkoxy- or benzyloxy-substituted 1-alkene 4.

The reaction between the aldehyde 1 and the organometallic reagent 2 isgenerally conducted at a temperature of from about 0° C. to about 100°C. under anhydrous conditions in the presence of a inert organicsolvent. Preferred reaction temperatures are subject to variationdepending, in part, upon the reactivity of the particular organometallicreagent employed. Among the organometallic reagents there may bementioned alkenylmagnesium halides and alkenyllithium compounds having aterminal double bond such as, for example, allylmagnesium bromide,allylmagnesium chloride, allylmagnesium iodide, 3-butenylmagnesiumbromide, allyllithium, and the like. Allylmagnesium bromide ispreferred. Suitable solvents for the reaction include ethers such asdiethyl ether, dioxane, tetrahydrofuran, and the like; and, dependingupon the stability of the organometallic reagent, aromatic hydrocarbonssuch as benzene, toluene, xylene, and the like. It should be noted,however, that a solvent selection is limited by the solubility of theparticular organometallic reagent employed. Ethereal solvents,particularly tetrahydrofuran, are preferred.

The alkoxy- or benzyloxy substituted 1-alkenes 4 are produced byreacting the hydroxy-substituted 1-alkene 3 with an alkyl or benzylhalide (e.g. benzyl bromide, benzyl chloride, benzyl iodide, methylbromide, ethyl bromide, and the like) under basic conditions. Among thebases which may be employed in this reaction are alkali metal hydrides,alkali metals, and the like, including, for example, sodium hydride,potassium hydride, sodium, and potassium. Sodium hydride is preferred.The reaction is generally conducted under anhydrous conditions in thepresence of an ethereal and/or dipolar aprotic solvent such astetrahydrofuran, dioxane, diethyl ether, bis(2-methoxyethyl) ether,1,2-dimethoxyethane, dimethylformamide, dimethylacetamide,dimethylsulfoxide, and hexamethylphosphoramide. Preferred solventsinclude tetrahydrofuran, dimethylformamide, and mixtures thereof.

Conversion of the alkoxy- or benzyloxy-substituted 1-alkene 4 to thecorresponding 1-alkanol 5 may be accomplished by reacting the 1-alkene 4with an appropriate hydroborating agent, followed by oxidation of theresulting borane to an alcohol 5. Among the hydroborating agents theremay be mentioned 9-borabicyclo[3.3.1]nonane, diborane, anddialkylboranes such as dimethyl borane, diethyl borane, and the like.9-Borabicyclo[3.3.1]nonane is preferred. Depending upon the activity ofthe hydroborating agent, the reaction is conducted under an inertatmosphere. For example, when the hydroborating agent is9-borabicyclo[3.3.1]nonane, it is recommended that the reaction beconducted under nitrogen. The hydroboration of the 1-alkene 4 isconducted at a temperature of from about 0° C. to about 50° C.,preferably from about 0° C. to about 20° C., in the presence of an inertorganic solvent. Suitable solvents include ethereal solvents, aromatichydrocarbons, halocarbons, and the like, such as, for example,tetrahydrofuran, diethylether, dioxane, benzene, toluene, xylene,dichloromethane, 1,1- and 1,2-dichloromethane, 1,1- and1,2-dichloroethane and the like. Ethereal solvents, particularlytetrahydrofuran are preferred. Oxidation of the borane is conventionallyaccomplished by treatment with alkaline hydrogen peroxide at atemperature of from about 0° C. to about 100° C. Preferred temperaturesfor the oxidation range from about 20° C. to about 50° C.

As illustrated by Reaction Scheme B, benzyloxy- or alkoxy-substitutedalkanols of the formula ##STR13## wherein R¹ is a phenyl or phenoxygroup, may be prepared by treating a 1-alkene 6 with ozone followed byan appropriate organometallic reagent to produce an hydroxy substituted1-alkene. Conversion of the hydroxy-substituted 1-alkene 3 to thecorresponding alkoxy- or benzyloxy-substituted 1-alkene 4, followed byhydration of the terminal double bond provides an alkoxy- orbenzyloxy-substituted alkan-1-ol 5. Treatment of the 1-alkene 6 withozone is generally conducted at temperatures of from about -70° C. toabout 0° C. in the presence of an anhydrous organic solvent. Suitablesolvents include aromatic hydrocarbons and ethereal solvents such asbenzene, toluene, xylene, diethyl ether, tetrahydrofuran dioxane and thelike. In general, toluene is the preferred solvent. Appropriateorganometallic reagents are as described in the context of ReactionScheme A. As organometallic reagents, Grignard reagents, particularlyallylmagnesium bromide, are preferred. In general, the organometallicreaction is conducted at a temperature of from about 0° C. to about 100°C., preferably from about 0° C. to about 65° C.

The hydroxy substituted alkene 3 is treated with an alkyl halide toproduce a benzyloxy- or alkoxy-substituted alkene 4, which is convertedto an alkan-1-ol, 5 via the corresponding borane, all as previouslydescribed in the context of Reaction Scheme A.

Reaction Scheme C illustrates an alternative synthesis for theproduction of benzyloxy- or alkoxy-substituted alkan-1-ols of theformula ##STR14## wherein R¹ is hydrogen. As shown by this scheme, analkyl metal halide 7 is reacted with a (tetrahydro-2H-pyran-2-yl)oxy-substituted aldehyde 8 to produce an hydroxy-substituted alkane 9,which is thereafter converted to the corresponding alkoxy orbenzyloxy-substituted alkane 10 and subsequently cleaved to analkan-1-ol 5.

The reaction of the alkyl metal halide 7 and aldehyde 8 is typicallyconducted under anhydrous conditions at a temperature of from about 0°C. to about 100° C. in the presence of an inert organic solvent.Preferred reaction temperatures range from about 0° C. to about 35° C.Among the appropriate solvents there may be mentioned ethereal solventssuch as dioxane, diethyl ether, tetrahydrofuran and the like. Diethylether is preferred. Conversion of the hydroxy-substituted alkane 9 tothe corresponding benzyloxy- or alkoxy-substituted alkan-1-ol 5 may beaccomplished by treatment with an alkyl or benzyl halide followed bycleavage of the (tetrahydro-2H-pyran-1-yl) oxy group of the alkoxy orbenzyloxy-substituted alkane 10. Treatment of the hydroxy-substitutedalkane 9 with an alkyl or benzyl halide is conveniently accomplishedunder basic conditions at a temperature of from about 0° C. to about100° C. in the presence of an inert organic solvent. Suitable solventsinclude ethereal solvents such as diethyl ether, dioxane,1,2-dimethoxyethane, tetrahydrofuran and the like, as well as polaraprotic solvents such as dimethylformamide, dimethylacetamide,dimethylsulfoxide, hexamethylphosphoramide, and the like.Tetrahydrofuran or dimethylformamide is preferred. Suitable basesinclude alkali metal hydrides such as sodium hydride, potassium hydride,and the like, and alkali metals such as sodium and potassium. Sodiumhydride is preferred. Optionally, the reaction is conducted in thepresence of a promoter such as, for example, tetrabutylammonium iodide.

Cleavage of the (tetrahydro-2H-pyran-1-yl) oxy group is achieved bytreatment of the alkoxy- or benzyloxy-substituted alkane 10 with anappropriate acid (e.g. hydrochloric acid, sulfuric acid, hydrobromicacid, and the like), preferably hydrochloric acid), at a temperature offrom about 0° to about 100° C., preferably from about 25 to about 50, inthe presence of a suitable organic solvent. Suitable solvents includealkanols such as, for example, methanol, ethanol, propanol, and thelike. Ethanol is preferred.

As shown by Reaction Scheme D, Formula I compounds wherein A¹ is --C₂ H₄-- may be prepared by phosphorylating an alkoxy- orbenzyloxy-substituted-alkan-1-ol 5 with2-chloro-2-oxo-1,3,2-dioxaphospholane 11, and reacting the resultantcyclic triester 12 with a tertiary amine 13 to form an alkylphospholipid14.

The phosphorylation of the substituted alkan-1-ol 5 (i.e. an alkanol ofthe formula ##STR15## wherein R¹ is hydrogen, a phenyl group, or aphenoxy group; see Reaction Schemes A, B and C) by reaction with2-chloro-2-oxo-1,3,2-dioxaphospholane 16 is generally conducted underanhydrous conditions at a temperature of from about 0° to about 100° C.in the presence of an inert organic solvent. Preferred temperatures forthe phosphorylation reaction range from about 0° to about 30° C.Suitable solvents include ethereal solvents such as, for example,dimethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like,aromatic hydrocarbons such as benzene, toluene, xylene and the like,halocarbons such as chloroform, methylene chloride; and the like, andmixtures thereof. The reaction is optionally conducted in the presenceof an acid acceptor. Among the suitable acid acceptors there may bementioned organic bases, such as, for example tertiary and heterocyclicamines (e.g., trimethyl, tripropyl, triethyl amine, pyridine, picoline,lutidine, collidine and the like). Mixtures of (a) triethylamine orpyridine and (b) tetrahydrofuran or toluene are preferred.

The conversion of the cyclic triester 12 to a phospholipid 14, istypically accomplished under anhydrous conditions in the presence of aninert organic solvent at a temperature of from about 0° C. to about 100°C., preferably from about 60° C. to about 80° C. In addition to theethereal and halocarbon solvents mentioned supra in connection with thephosphorylation reaction, suitable solvents include polar aproticsolvents such as dimethylformamide, dimethylacetamide,hexamethylphosphoramide and the like, and acetonitrile. Acetonitrile ispreferred. Selection of the tertiary amine 13 is determined in part bythe quaternary group desired in the resultant alkylphospholipid 14.Among the tertiary amines 13 are aliphatic amines such as, for example,trimethylamine, triethylamine, N,N-dimethylethyl amine and the like; andheterocyclic amines such as, for example, N-alkyl pyrrolidines,piperidines, piperazines, morpholines, thiomorpholines and the like,such as, for example, N-methylpyrrolidine, N-ethylpyrrolidine,N-methylpiperidine, N-methylpiperazine, 1,4-dimethylpiperazine,4-methylmorpholine, 4-ethylmorpholine, and the like. Trimethylamine andN-methylpyrrolidine are preferred.

Benzyloxy-substituted alkylphospholipids 14 are converted to thecorresponding hydroxy-substituted alkylphospholipids 15 by hydrogenationin the presence of an appropriate catalyst. The hydrogenation reactionis conducted at a temperature from about 15° C. to about 100° C. and ahydrogen gas pressure of from about 1 atmosphere to about 10 atmospheresin an appropriate solvent. Hydrogenation temperatures of from about 20°C. to about 30° C. and hydrogen gas pressures of from about 1 atmosphereto about 4 atmospheres are preferred. Among the suitable solvents forthe hydrogenation reaction are alkanols, including methanol, ethanol,2-propanol, and the like; alkanoic acids, including formic acid, aceticacid and propanonic acid and the like; and the alkyl esters of theaforementioned alkanoic acids. Preferred solvents are ethanol, mixturesof ethanol and acetic acid, and mixtures of ethanol and ethyl acetate.Catalysts include nobel metals (e.g. palladium, platinum and rhodium).5% palladium on carbon is preferred.

Alternatively, as shown in Reaction Scheme E, compounds wherein A¹ is abivalent radical of the formula --C_(p) H_(2p) -- wherein p is aspreviously defined may be prepared by reacting an alkoxy- or benzyloxysubstituted alkan-1-ol 5 with an appropriate phosphorylating agent 16,followed by quaternization of the resultant phosphate diester 17 to analkylphospholipid 18. Included among the phosphorylating agents suitablefor use herein are haloalkylphosphorodichloridates such as2-bromoethylphosphorodichloridate, 2-chloroethylphosphorodichloridate,2-iodoethylphosphorodichloridate, 4-bromobutylphosphorodichloridate,6-bromohexylphosphodichloridate and the like. The phosphorylationreaction is generally conducted under anhydrous conditions in thepresence of a basic organic solvent. Basic organic solvents includealiphatic and heterocyclic tertiary amines such as trimethylamine,triethylamine, pyridine, and the like. The reaction may be conducted inthe presence of an appropriate co-solvent. Suitable co-solvents includeetheral solvents such as diethyl ether, dioxane, tetrahydrofuran and thelike; aromatic hydrocarbons such as benzene, toluene, xylene and thelike; and halocarbons such as dichloroethane, chloroform methylenechloride, and the like. Mixtures of triethylamine or pyridine anddiethyl ether are preferred. The phosphorylation reaction may beconducted at a temperature of from about 0° C. to about 25° C. Preferredreaction temperatures are subject to variation depending upon thereactivity of the particular reactants employed.

Quaternization of the phosphate diester 17 to the alkylphospholipid 18is conveniently accomplished under hydrous or anhydrous conditionsutilizing the tertiary amines previously described in Reaction Scheme D.Trimethylamine and N-methylpyrrolidine are preferred. The quaternizationreaction may be conducted at a temperature of from about 20° C. to about100° C., in the presence of an appropriate solvent. Among the suitablesolvents there may be mentioned polar aprotic solvents such asdimethylacetamide, dimethylformamide, hexamethyl phosphoramide, dimethylsulfoxide and the like; halocarbons such as dichloromethane, chloroform,dichloroethane and the like; ethereal solvents such as diethyl ether,dioxane, tetrahydrofuran and the like, alkanols such as methanol,ethanol, 1- and 2-propanol and the like; acetonitrile and the like; andmixtures thereof. Acetonitrile and mixtures of acetonitrile andisopropanol are preferred. Desirably, water is present as a co-solvent.Preferably the reaction is conducted at the reflux temperature of thesolvent medium and the resultant adduct is treated with silver carbonateto generate the desired product 18. Hydrogenation of thebenzyloxy-substituted phospholipid 18, under conditions as previouslydescribed, forms the corresponding hydroxy-substituted alkylphospholipid19.

It is a purpose of this invention to provide a method of treating and/orpreventing phospholipase A₂ mediated inflammatory and related conditionsby inhibiting the lipolytic ability of phospholipase A₂. PhospholipaseA₂, an enzyme involved in phospholipid degradation as well as variousmetabolic regulatory processes, has been linked to the initiation of thearachidonic acid cascade. Derivatives produced by the various enzymes ofthe cascade include prostaglandins, eicosatetraenoic acids,eicosatrienoic acids, thromboxanes and leukotrienes. The presence ofseveral of these hydroxylated derivatives is associated with diseases orconditions which include systemic inflammation, ocular inflammation,dermal inflammation, rheumatoid arthritis, erythema and allergicresponses (e.g. asthma, hay fever, etc.). Blocking the production ofsuch derivatives as a means of suppressing inflammatory conditions inanimal models is disclosed, for example, by R. J. Flower, in Nature,Vol. 320, p. 201, Mar. 6, 1986.

The phospholipase A₂ inhibiting ability of the compounds of thisinvention was evaluated by means of a modification of the assayprocedure disclosed by H. S., Hendrickson, E. K., and Dybvig, R. H. inChiral Synthesis of a Ditholester Analog of Phosphatidylcholine as aSubstrate for the Assay of Phospholipase A₂, Journal of Lipid Research,Vol. 24, pp 1532-1537 (1983) (hereinafter "Hendrickson et al."). Thesubstrate employed in the modified assay, was1,2-bis(decanoylthio)-1,2-dideoxyglycerol-3-phosphocholine (hereinafter"Thio Pc Substrate"). The enzyme utilized in the procedure wasphospholipase A₂ isolated from rat perotoneum as follows:

Male Wistar rats weighing 200-300 g a piece were injectedinterperitoneally at a dosage of 50 ml/kg of body weight (20 g of caseinas the sodium salt diluted to 500 ml in distilled water). After a periodof 18-24 hours the animals were sacrificed. Thereafter, each animal wasinjected interperitoneally with 30 ml of an isotonic salt solution towhich sodium heparin was added prior to use at a concentration of 5units/ml. Enzyme-containing exudate was aspirated through an abdominalincision. Separation of the enzyme from the exudate was accomplished bycentrifugation.

Pursuant to the assay procedure, Thio Pc Substrate was apportioned into1.25 mg aliquots. To each aliquot was added 4 ml of 160 mM tris hydrogenchloride buffer (pH 7.5) containing 2 mM of calcium chloride and 2 mM ofsodium taurocholate. The resulting dispersions were vortexed at roomtemperature to clear solutions. Inhibition activity of thealkylphospholipids of this invention was determined utilizingspectrophotometric samples prepared by the addition of 5 ul of4,4'dithiopyridine and 395 ml of buffered Thio Pc substrate to aperincubated dispersion of 50 ul of alkylphospholipid (appropriatelydiluted in buffer) in 50 ul of enzyme (appropriately diluted in buffer).Absorbence at (0.5 full scale) was recorded at a chart speed of 2 cm/minon a Gilford Model 250 Spectrophotometer.

The percentage of phospholipase A₂ inhibition was calculated by means ofthe following formula: ##EQU1## wherein "inhibitor slope" is the slopeof the spectrophotometric curve obtained for a givenalkylphospholipid-containing sample and "control slope" is the slope ofthe spectrophotometric curve obtained for an otherwise identical samplelacing an inhibitor.

The phospholipase A₂ -inhibiting ability of several of the compounds ofthis invention are provided in the following Table:

                  TABLE 1                                                         ______________________________________                                        Compound            % PLA.sub.2 Inhibition                                    ______________________________________                                        4-hydroxy-N,N,N-trimethyl-9-                                                                      41.8% @ 1.0 × 10.sup.-4 M                           phenylmethoxy-3,5-dioxa-4-                                                    phosphatetracosan-1-aminium,                                                  4-oxide, hydroxide, inner salt                                                monohydrate                                                                   4,9-dihydroxy-N,N,N-trimethyl-3,5-                                                                45.6% @ 1.0 × 10.sup.-4 M                           dioxa-4-phosphatetracosan-1-aminium,                                          4-oxide, hydroxide, inner salt                                                sesquihydrate                                                                 4-hydroxy-N,N,N-trimethyl-9-                                                                      *IC.sub.50 = 8.4 × 10.sup.-5 M                      phenylmethoxy-3,5-dioxa-4-                                                    phosphahexacosan-1-aminium,                                                   4-oxide, hydroxide, inner salt                                                monohydrate                                                                   4,9-dihydroxy-N,N,N-trimethyl-                                                                    *IC.sub.50 = 9.5 × 10.sup.-5 M                      3,5-dioxa-4-phosphapentacosan-1-                                              aminium, 4-oxide, hydroxide,                                                  inner salt monohydrate                                                        Quinacrine          *IC.sub.50 = 3.1 × 10.sup.-5 M                      ______________________________________                                         *wherein IC.sub.50 is that concentration of inhibitor which reduces           enzymatic activity by 50%                                                

Thus, the products of the present invention are useful to inhibitphospholipase A₂ in a mammalian system whenever it is deemed necessaryor desirable. They are especially useful in treating symptoms orconditions resulting from excessive stimulation of the arachidonic acidcascade during certain disease processes or conditions such asinflammation, erythema and allergic responses.

Although the precise mechanisms of the disease processes or conditionswhich stimulate the arachidonic acid cascade are not clearly understood,the essential prerequisite appears to be an enhanced activity of thephospholipases which provide arachidonate to the series of biochemicalreactions designated as the arachidonic acid cascade. The method of thisinvention is simply to block the action of the phospholipases and cutoff the flow of arachidonate into the cascade, irrespective of thestimuli which may be present. This can be accomplished by compounds ofthe present invention. Thus, the method of this invention is suitablefor treating a myriad of seemingly unrelated diseases whose commonelement is the stimulation of the arachidonic cascade.

The phospholipids of the invention are effective in the treatment ofphospholipase A₂ mediated inflammatory conditions when administeredorally, peritoneally, intraveneously or topically to a subject requiringsuch treatment at a dose of from about 0.1 to about 60 mg/kg of bodyweight per day.

It is to be understood that specific dosage regimens should be adjustedaccording to the individual need of a particular subject and theprofessional judgement of the person administering or supervising theadministration of the compounds of this invention. Individualrequirements will depend on factors which include the particularphospholipase A₂ mediated inflammatory condition being treated and itsseverity; the age, weight, physical condition, and sex of the subject;as well as the particular administrative method(s) employed.

The compounds of the present invention are also useful as analgesicagents due to their ability to alleviate pain in mammals. The activityof the compounds is demonstrated in the phenyl-para-quinone writhingassay in mice, a standard assay for analgesia [Proc. Soc. Exptl. Biol.Med., 95, 729 (1957)]. Presented in Table 2 is the analgesic effect ofsome of the compounds of the invention expressed as either thesubcutaneous dose at which 50% of the phenyl-para-quinone inducedwrithing is inhibited in the animals, i.e., the ED₅₀ value, or as the %decrease in writhing at a give dose.

                  TABLE 2                                                         ______________________________________                                                              Analgesic PQW                                                                 % Inhibition of                                                               Writhing at                                             Compound              20 mg/kg, s.c.                                          ______________________________________                                        4-hydroxy,N,N,N-trimethyl-9-                                                                        83%                                                     phenylmethoxy-3,5-dioxa-4-                                                    phosphaoctadecan-1-aminium,                                                   4-oxide, hydroxide, inner salt                                                monohydrate                                                                   4-hydroxy-N,N,N-trimethyl-9-                                                                        36%                                                     phenylmethoxy-3,5-dioxa-4-                                                    phosphatetracosan-1-aminium,                                                  4-oxide, hydroxide, inner salt                                                monohydrate                                                                   4,9-dihydroxy-N,N,N-trimethyl-3,5-                                                                  48%                                                     dioxa-18-phenoxy-4-phosphaoctadecan-                                          1-aminium, 4-oxide, hydroxide,                                                inner salt dihydrate                                                          4,9-dihydroxy-N-methyl-3,5-dioxa-4-                                                                 62%                                                     phosphatetracosan-1-pyrrolidinium,                                            4-oxide, hydroxide, inner salt                                                3.5 hydrate                                                                   Propoxyphene (reference compound)                                                                   50% at                                                                        3.9 mg/kg, s.c.                                         ______________________________________                                    

The analgesic relief of pain is achieved when the compounds of theinvention are administered to a subject requiring such treatment at aneffective oral, parenteral or intravenous dose of from 0.01 to 100 mg/kgof body weight per day. A preferred effective dose within this range isfrom about 10 to 50 mg/kg of body weight per day. A particularlypreferred effective amount is about 30 mg/kg of body weight per day. Itis to be understood, however, that for any particular subject, specificdosage regimens should be adjusted according to the individual need andthe professional judgement of the person administering or supervisingthe administration of the compound. It is further to be understood thatthe dosages set forth herein are exemplary only and that they do not, toany extent, limit the scope or practice of the invention.

For the purpose of oral therapeutic administration, the aforesaidcompounds may be incorporated with excipients, diluents and/or carriersand used in the form of tablets, troches, capsules, elixirs,suspensions, syrups, wafers, chewing gums and the like. Thesepreparations should contain at least 0.5% of active compound, but may bevaried depending upon the particular form and may conveniently bebetween 4% and 70% of the weight of the unit. The amount of activecompound is such that a suitable dosage will be obtained. Preferredcompositions and preparations according to the present invention areprepared so that an oral dosage form contains between 1.0 and 300milligrams of the active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, corn starch and the like; alubricant such as magnesium stearate; a glidant such as colloidalsilicon dioxide; and a sweetening agent such as sucrose or saccharin ora flavoring agent such as peppermint, methyl salicylate, or orangeflavoring may be aded. When the dosage unit form is a capsule, it maycontain, in addition to materials of the above type, a liquid carriersuch as a fatty oil. Other dosage unit forms may contain other variousmaterials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral or topical therapeutic administration,the active compounds of the invention may be incorporated into asolution, suspension, ointment or cream. These preparations shouldcontain at least 0.1% of active compound, but may be varied between 0.5and about 50% of the weight thereof. The amount of active compounds insuch compositions is such that a suitable dosage will be obtained.Preferred compositions and preparations according to the presentinvention are prepared so that a parenteral or topical dosage unitcontains between 0.5 and 100 milligrams of active compound.

The solutions or suspensions for topical or parenteral administrationmay also include the following components: a sterile diluent such aswater for injection, saline solution, fixed oils, polyethylene glycols,glycerine, propylene glycol or other synthetic solvents; antibacterialagents such as benzyl alcohol or methyl parabens; antioxidants such asascorbic acid or sodium bisulfite; chelating agents such asethylenediaminetetraacetic acid; buffers such as acetates, citrates orphosphates and agents for the adjustment of tonicity such as sodiumchloride or dextrose. The parenteral preparation can be enclosed inampules or disposable syringes; the topical preparation may be enclosedin multiple dose vials or dropping bottles, made of glass or plastic.

Included among the compounds of this invention are:

4-hydroxy-N,N,N-trimethyl-9-methoxy-3,5-dioxa-18-phenoxy-4-phosphaoctadecan-1-aminium,4-oxide, hydroxide inner salt;

5-hydroxy-N,N,N-trimethyl-10-phenylmethoxy-4,6-dioxa-18-phenyl-5-phosphanonadecan-1-aminium,5-oxide, hydroxide inner salt;

5,10-dihydroxy-N,N,N-trimethyl-4,6-dioxa-5-phosphanonadecan-1-aminium,5-oxide, hydroxide inner salt;

6,11-dihydroxy-N,N,N-trimethyl-5,7-dioxa-6-phosphatetracoden-1-aminium,6-oxide, hydroxide, inner salt;

4-hydroxy-1-methyl-3,5-dioxa-9-phenylmethoxy-4-phosphaoctadecan-1-piperidium,4-oxide, hydroxide, inner salt;

4,9-dihydroxy-N,N,N-trimethyl-3,5-dioxa-4-phosphatridecan-1-aminium,4-oxide, hydroxide, inner salt;

4-hydroxy-N,N,N-trimethyl-9-methoxy-N,N,N-trimethyl-3,5-dioxa-4-phosphatridecan-1-aminium,4-oxide, hydroxide, inner salt;

4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-4-phosphatridecan-1-aminium,4-oxide, hydroxide, inner salt;

4-hydroxy-N,N,N-trimethyl-9-(4-methylphenyl)methoxy-3,5-dioxa-4-phosphatridecan-1-aminium,4-oxide, hydroxide, inner salt;

4-hydroxy-N,N,N-trimethyl-9-(4-chlorophenyl)methoxy-3,5-dioxa-4-phosphatridecan-1-aminium,4-oxide, hydroxide, inner salt;

4,9-dihydroxy-N-methyl-3,5-dioxa-4-phosphatridecan-1-pyrrolidinium,4-oxide, hydroxide, inner salt;

4,9-dihydroxy-N-methyl-3,5-dioxa-4-phosphatridecan-1-piperidium,4-oxide, hydroxide, inner salt;

4,9-dihydroxy-N-methyl-N'-phenyl-3,5-dioxa-4-phosphatridecan-1-piperazinium,4-oxide, hydroxide, inner salt;

4,9-dihydroxy-N-methyl-3,5-dioxa-4-phosphatridecan-1-(4-morpholinium),4-oxide, hydroxide, inner salt;

4,9-dihydroxy-N-methyl-3,5-dioxan-4-phosphatridecan-1-(4-thiomorpholinium),4-oxide, hydroxide, inner salt;

4,10-dihydroxy-N,N,N-trimethyl-3,5-dioxa-4-phosphatetradecan-1-aminium,4-oxide, hydroxide, inner salt;

4-hydroxy-N,N,N-trimethyl-10-ethoxy-N,N,N-trimethyl-3,5-dioxa-4-phosphatetradecan-1-aminium,4-oxide, hydroxide, inner salt;

4-hydroxy-N,N,N-trimethyl-10-phenylmethoxy-3,5-dioxa-4-phosphatetradecan-1-aminium,4-oxide, hydroxide, inner salt;

4-hydroxy-N,N,N-trimethyl-10-(4-methoxyphenyl)methoxy-3,5-dioxa-4-phosphatetradecan-1-aminium,4-oxide, hydroxide, inner salt;

4-hydroxy-N,N,N-trimethyl-10-[4-(trifluoromethyl)phenyl]methoxy-3,5-dioxa-4-phosphatetradecan-1-aminium,4-oxide, hydroxide, inner salt;

4,10-dihydroxy-N-methyl-3,5-dioxa-4-phosphatetradecan-1-pyrrolidinium,4-oxide, hydroxide, inner salt;

4,9-dihydroxy-N,N,N-trimethyl-3,5-dioxa-13-phenyl-4-phosphatridecan-1-aminium,4-oxide, hydroxide, inner salt;

4,9-dihydroxy-N,N,N-trimethyl-3,5-dioxa-13-phenoxy-4-phosphatridecan-1-aminium,4-oxide, hydroxide, inner salt;

4,9-dihydroxy-N-methyl-3,5-dioxa-13-phenyl-4-phosphatridecan-1-pyrrolidinium,4-oxide, hydroxide, inner salt;

4,10-dihydroxy-N,N,N-trimethyl-3,5-dioxa-14-phenyl-4-phosphatetradecan-1-aminium,4-oxide, hydroxide, inner salt;

6,11-dihydroxy-N,N,N-trimethyl-5,7-dioxa-6-phosphaheptadecan-1-aminium,6-oxide, hydroxide, inner salt;

6-hydroxy-N,N,N-trimethyl-11-phenylmethyl-4,6-dioxa-6-phosphaheptadecan-1-aminium,6-oxide, hydroxide, inner salt;

6,11-dihydroxy-N-methyl-5,7-dioxa-6-phosphaheptadecan-1-pyrrolidinium,6-oxide, hydroxide, inner salt;

6-hydroxy-11-methoxy-N-methyl-5,7-dioxa-6-phosphaheptadecan-1-pyrrolidinium,6-oxide, hydroxide, inner salt;

6-hydroxy-11-methoxyphenyl-N-methyl-5,7-dioxa-17-phenyl-6-phosphaheptadecan-1-pyrrolidinium,6-oxide, hydroxide, inner salt;

5,11-dihydroxy-N,N,N-trimethyl-4,6-dioxa-5-phosphadocosan-1-aminium,5-oxide, hydroxide, inner salt;

5,11-dihydroxy-N,N,N-trimethyl-4,6-dioxa-22-phenyl-5-phosphadocosan-1-aminium,5-oxide, hydroxide, inner salt;

5-hydroxy-N,N,N-trimethyl-11-phenylmethoxy-4,6-dioxa-5-phosphadocosan-1-aminium,5-oxide, hydroxide, inner salt;

5-hydroxy-N-methyl-11-phenylmethoxy-4,6-dioxa-22-phenyl-5-phosphadocosan-1-aminium,5-oxide, hydroxide, inner salt;

5-hydroxy-N-methyl-11-(2,4-difluorophenyl)methoxy-4,6-dioxa-5-phosphadocosan-1-piperidium,5-oxide, hydroxide, inner salt;

4,9-dihydroxy-N,N,N-trimethyl-3,5-dioxa-4-phosphaheptacosan-1-aminium,4-oxide, hydroxide, inner salt;

4,9-dihydroxy-N,N,N-trimethyl-3,5-dioxa-28-phenyl-4-phosphaheptacosan-1-aminium,4-oxide, hydroxide, inner salt; and

8,13-dihydroxy-N,N,N-trimethyl-7,9-dioxa-8-phosphahentriacontan-1-aminium,8-oxide, hydroxide, inner salt.

EXAMPLES

The following Examples are for illustrative purposes only and are not tobe construed as limiting the invention. All temperatures are given indegrees centigrade (°C.). With the exception of yields which arecalculated on a molar basis, all percentages are by volume, unlessotherwise noted.

EXAMPLE 14-Hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-4-phosphaoctadecan-1-aminium,4-oxide, hydroxide, inner salt monohydrate Step 1

A solution of 10 g of 1-tridecen-4-ol in 100 ml of tetrahydrofuran wasadded, dropwise, under nitrogen to hexane-washed sodium hydride (from3.15 g of a 50% oil dispersion). The mixture was stirred at 50° and asolution of 6.6 ml of benzyl bromide in 50 ml of dimethylformamide wasadded, dropwise. The reaction mixture was refluxed for 3 hrs., cooled,quenched by the addition of 25 ml of water, and concentrated. Theconcentrate was extracted three times with 100 ml aliquots ofhexane/diethyl ether (2:1 by volume). The combined extracts were washedwith 100 ml of water and 100 ml of a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate andconcentrated. Purification of the concentrate by flash chromatography onsilica gel utilizing 1% diethyl ether/hexane as an eluent yielded 11.77g (81%) of 4-benzyloxy-1-tridecene as an oil.

ANALYSIS: Calculated for C₂₀ H₃₂ O: 83.27%C; 11.18%H. Found: 83.46%C;11.21%H.

Step 2

A solution of 9.3 g of 4-benzyloxy-1-tridecene in 40 ml oftetrahydrofuran was added, dropwise, under nitrogen, to 70.4 ml of9-borabicyclo[3.3.1]nonane (0.5M solution in hexane). The reactionmixture was stirred at room temperature for 3 hrs. and quenched by thesequential addition of 18 ml of ethanol, 6 ml of 6N sodium hydroxide,and 12 ml of 30% hydrogen peroxide. The reaction mixture was heated at50° for 2 hrs. and then allowed to stand at ambient temperatureovernight. Upon standing the mixture separated into aqueous and organicphases. The aqueous phase was saturated with potassium carbonate and theorganic phase was separated, washed with 30 ml of a 10% aqueous solutionof sodium sulfite and 30 ml of a saturated aqueous solution of sodiumchloride, dried over anhydrous potassium carbonate, and concentrated.The residue was taken up in 20% diethyl ether/hexane, filtered, andconcentrated to an oil. Flash chromatography of the oil on silica gelusing hexane diethyl ether (2:1 by volume) as the eluent yielded 7.7 g(80%) of 4-benzyloxytridecan-1-ol as an oil.

ANALYSIS: Calculated for C₂₀ H₃₄ O₂ : 78.38%C; 11.18%H. Found: 76.65%C;11.45%H.

Step 3

To a stirred solution of 18.2 g of 2-bromoethyl phosphorodichloridate in400 ml of diethyl ether, cooled to 0°, was added, dropwise, in thefollowing order, 30 ml of pyridine, and a solution of 11.48 g of4-benzyloxytridecan-1-ol in 400 ml of diethyl ether. Upon the completionof the addition, the reaction mixture was stirred for 30 minutes at 0°,warmed to room temperature, diluted with water and acidified to a pH of2 by the addition of 6N hydrochloric acid. Upon standing the reactionmixture separated into aqueous and organic layers. The organic layer waswashed with 100 ml of a saturated solution of sodium chloride, driedover anhydrous magnesium sulfate, and concentrated. The concentrate waspurified by high pressure liquid chromatography utilizing 6%methanol/dichloromethane as the eluent to give 11.48 g (62%) of2-bromoethyl 4-benzyloxytridecan-1-yl phosphate as a solid.

ANALYSIS: Calculated for C₂₂ H₃₈ PO₅ Br: 53.55%C; 7.76%H; 6.28%P. Found:53.30%C; 7.52%H; 6.41%P.

Step 4

To a solution of 10.22 g of 2-bromoethyl 4-benzyloxytridecan-1-ylphosphate in 92 ml of trichloromethane was added, dropwise in thefollowing order, 149 ml of isopropyl alcohol, 149 ml of acetonitrile,and 290 ml of a 33% aqueous solution of trimethylamine. The reactionmixture was stirred at 55° for 20 hrs., cooled and concentrated. Theresidue was taken up in 250 ml of methanol, refluxed with 8 g of silvercarbonate for 2 hrs, filtered and concentrated. The concentrate waspurified by means of flash chromatography using as successive eluentschloroform/methanol (9:1 by volume), chloroform/methanol (4:1 byvolume), and chloroform/methanol/water (120:30:4 by volume).

Azeotroping with toluene followed by standing overnight yielded 4.32 g(52%) of4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-4-phosphaoctadecan-1-aminium,4-oxide, hydroxide, inner salt monohydrate.

ANALYSIS: Calculated for C₂₅ H₄₆ NO₅ P.H₂ O: 61.32%C; 9.88%H; 2.86%N;6.33%P. Found: 61.07%C; 9.79%H; 2.84%N; 6.24%P.

EXAMPLE 24,9-Dihydroxy-N,N,N-trimethyl-3,5-dioxa-4-phosphaoctadecan-1-aminium,4-oxide, hydroxide, inner salt trihydrate

A mixture of 3.26 g of4-hydroxy-N,N,N-trimethyl-7-phenylmethoxy-3,5-dioxa-4-phosphaoctadecan-1-aminium,4-oxide, hydroxide, inner salt monohydrate (prepared as in Example 1),100 ml of ethanol, 50 ml of ethyl acetate and 0.5 g of 5% palladium oncarbon was hydrogenated for 13 hrs. at 50 psi. The reaction mixture wasfiltered and concentrated. The concentrate was purified by flashchromatography on silica gel using as successive eluentschloroform/methanol (9:1 by volume) and chloroform/methanol/water(120:30:4 by volume) to yield 0.96 g (35%) of4,9-dihydroxy-N,N,N-trimethyl-3,5-dioxa-4-phosphaoctadecan-1-aminium,4-oxide, hydroxide, inner salt trihydrate, mp 235°-239°.

ANALYSIS: Calculated for C₁₈ H₄₀ NO₅ P 3H₂ O: 49.64%C; 10.65%H; 3.20%N;7.11%P. Found: 49.31%C; 10.12%H; 3.15%N; 6.75%P.

EXAMPLE 34-Hydroxy-1-methyl-3,5-dioxa-9-phenylmethoxy-4-phosphaoctadecan-1-pyrrolidinium,4-oxide, hydroxide, inner salt tetrahydrate

To a stirred, anhydrous solution of 6 g of 4-benzyloxytridecan-1-ol(prepared as in Step 2 of Example 1) in 3.3 ml of triethylamine and 200ml of toluene was added dropwise, under nitrogen, 2.8 g of2-chloro-2-oxo-1,3,2-dioxaphospholane. The reaction mixture was stirredat ambient temperature overnight, filtered and concentrated. The residuewas dissolved in 115 ml of acetonitrile, combined with 5.1 g ofN-methylpyrrolidine, refluxed for 40 hrs. and concentrated. The residuewas purified by flash chromatography using as successive eluentschloroform/methanol (9:1 by volume) followed bychloroform/methanol/water (120:30:4 by volume) to yield 5.8 g (59%) of4-hydroxy-1-methyl-3,5-dioxa-9-phenylmethoxy-4-phosphaoctadecan-1-pyrrolidinium,4-oxide, hydroxide, inner salt tetrahydrate as a gum.

ANALYSIS: Calculated for C₂₇ H₄₈ NO₅ P 4H₂ O: 56.92%C; 9.91%H; 2.46%N;5.43%P. Found: 57.40%C; 9.66%H; 2.39%N; 5.71%P.

EXAMPLE 44-Hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-4-phosphatetracosan-1-aminium,4-oxide, hydroxide, inner salt monohydrate Step 1

To 93 ml of a solution of allylmagnesium bromide in diethylether (1.0M)was added, dropwise, a solution of 26 g of hexadecanal in 120 ml oftetrahydrofuran while maintaining a temperature of less than 30°.Following the addition, the reaction mixture was stirred for 16 hours atambient temperature, poured onto ice, and diluted with a saturatedaqueous ammonium chloride. Evaporation of the organic phase yielded aslurry. The slurry was acidified to a pH of 2 by the addition of 9Msulfuric acid, and extracted with ethyl ether. The extract was washedwith water until neutral, with a saturated solution of sodium chloride,dried over anhydrous sodium sulfate, and evaporated to give 28 g of anoil. High pressure liquid chromatography of the oil yielded 13.3 g of1-nonadecen-4-ol as a wax, mp 37°-39.5°.

ANALYSIS: Calculated for C₁₉ H₃₈ O: 80.78%C; 13.56%H. Found: 80.88%C;13.52%H.

Step 2

To a solution of 11.0 g of 1-nonadecen-4-ol in 60 ml ofdimethylformamide was added hexane-washed sodium hydride (from 2.34 g ofa 50% oil dispersion). The reaction mixture was heated to 50° and 4.6 mlof benzyl bromide was added. The mixture was cooled to room temperature,quenched by the addition of water, and concentrated. The concentrate wasdiluted with water and then extracted with diethyl ether. The combinedextracts were washed with water, dried over anhydrous sodium sulfate andconcentrated to an oil. Purification of the oil by high pressure liquidchromatography utilizing diethyl ether/hexane (1:99) yielded 10.5 g(72%) of 4-benzyloxy-1-nonadecene as a liquid.

ANALYSIS: Calculated for C₂₆ H₄₄ O: 83.80%C; 11.90%H. Found: 83.29%C;11.88%H.

Step 3

To 66 ml of a 0.5M solution of 9-borabicyclo[3.3.1]nonane intetrahydrofuran, was added dropwise, under nitrogen, a solution of 11.1g of 4-benzyloxy-1-nonadecene in 20 ml of dry tetrahydrofuran. Thereaction mixture was stirred at room temperature for 2 hours, thenquenched by the successive addition of 18 ml of ethanol, 6 ml of 6Nsodium hydroxide solution, and 13 ml of 30% hydrogen peroxide. Themixture was maintained at 50° for 2 hours. Upon standing the mixtureformed aqueous and organic phases. The aqueous phase was saturated withpotassium carbonate, and the organic phase was separated, washed with 25ml of a 10% aqueous solution of sodium sulfite and 25 ml of a saturatedaqueous solution of sodium chloride, dried over anhydrous potassiumcarbonate, and concentrated. The concentrate was taken up in 20% diethylether/hexane, filtered and concentrated to give 11.5 g of an oil. Flashchromatography of the oil on silica gel using as an eluenthexane/diethyl ether (2:1 by volume) yielded 10.3 g of4-benzyloxynonadecan-1-ol as an oil.

ANALYSIS: Calculated for C₂₆ H₄₆ O₂ : 79.94%C; 11.87%H. Found: 80.00%C;12.04%H.

Step 4

A reaction mixture formed by the dropwise addition of 3.65 g of neat2-chloro-2-oxo-1,3,2-dioxaphospholane to an anhydrous solution of 10.0 gof 4-benzyloxynonadecan-1-ol and 4.2 ml of triethylamine in 200 ml oftoluene was stirred at room temperature overnight, filtered, andconcentrated to give 11.9 g of an oil. The oil was dissolved in 150 mlof acetonitrile and added to a pressure reactor. Trimethylamine (9 g)was condensed into the reactor, under nitrogen, at about -15°. Thereactor was then sealed and heated at 70°-80° for 24 hours. Cooling thereaction mixture in ice precipitated a solid. The solid was collected,washed with acetone, taken up in chloroform/benzene and concentrated toa residue. The residue was purified by flash chromatography on silicausing as successive eluents chloroform/methanol (9:1 by volume) andchloroform/methanol/water (120:30:4 by volume) to give 7.4 g of4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-4-phosphatetracosan-1-aminium,4-oxide, hydroxide, inner salt monohydrate, as a waxy solid.

ANALYSIS: Calculated for C₃₁ H₅₈ NO₅ P.H₂ O: 64.89%C; 10.54%H; 2.44%N;5.39%P. Found: 65.29%C; 10.46%H; 2.45%N; 5.05%P.

EXAMPLE 54-Hydroxy-N-methyl-3,5-dioxa-9-phenylmethoxy-4-phosphatetracosan-1-pyrrolidinium,4-oxide, hydroxide, inner salt dihydrate

To an anhydrous solution of 10 g of 4-benzyloxynonadecan-1-ol (preparedas in Step 2 of Example 4) and 4.2 ml of triethylamine in 200 ml oftoluene was added dropwise, under nitrogen, 3.65 g of2-chloro-2-oxo-1,3,2-dioxaphospholane. The mixture was stirred at roomtemperature overnight, filtered, and concentrated. The residue wascombined with 8.0 ml of N-methylpyrrolidine and 120 ml of anhydrousacetonitrile, and refluxed under nitrogen for 28 hours. Concentration ofthe mixture gave 17.4 g of an oil. Flash chromatography of the oil usingas successive eluents chloroform/methanol (9:1 by volume) andchloroform/methanol/water (120:30:4 by volume) gave 9.4 g of4-hydroxy-N-methyl-3,5-dioxa-9-phenylmethoxy-4-phosphatetracosan-1-pyrrolidinium,4-oxide, hydroxide, inner salt dihydrate as a wax.

ANALYSIS: Calculated for C₃₃ H₆₀ NO₅ P.2H₂ O: 64.15%C; 10.44%H; 2.27%N;5.16%P. Found: 63.92%C; 10.16%H; 2.61%N; 5.18%P.

EXAMPLE 64,9-Dihydroxy-N-methyl-3,5-dioxa-4-phosphatetetracosan-1-pyrrolidinium,4-oxide, hydroxide, inner salt 3.5 hydrate

A solution of 4.3 g of4-hydroxy-N-methyl-3,5-dioxa-9-phenylmethoxy-4-phosphatetracosan-1-pyrrolidinium,4-oxide, hydroxide, inner salt dihydrate (prepared as in Example 5) in125 ml of ethanol and 60 ml of acetic acid was hydrogenated in a Parrapparatus in the presence of 0.6 g of 5% palladium-on-carbon at 25 psifor 16 hours. Filtration, concentration and azeotroping withchloroform/toluene yielded a residue which was triturated with 200 ml ofdiethyl ether/hexane (1:1 by volume) to give 3.2 g of a solid. Flashchromatography of the solid using as successive eluentschloroform/methanol (9:1 by volume) and chloroform/methanol/water(120:30:4 by volume) gave 2.7 g of4,9-dihydroxy-N-methyl-3,5-dioxa-4-phosphatetracosan-1-pyrrolidinium,4-oxide, hydroxide, inner salt 3.5 hydrate as a solid.

ANALYSIS: Calculated for C₂₆ H₅₄ NO₅ P.3.5H₂ O: 56.29%C; 11.08%H;2.52%N; 5.58%P. Found: 56.58%C; 10.49%H; 2.54%N; 5.65%P.

EXAMPLE 74,9-Dihydroxy-N,N,N-trimethyl-3,5-dioxa-4-phosphatetracosan-1-aminium,hydroxide, inner salt sesquihydrate

A solution of 4.9 g of4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-4-phosphatetracosan-1-aminium,4-oxide, hydroxide, inner salt monohydrate in 150 ml of ethanol wastreated overnight, at room temperature in an atmospheric hydrogenator inthe presence of 0.6 g of 5% palladium on carbon. A volume of 217 ml ofhydrogen was consumed. The solution was filtered, diluted with 10 ml ofwater, and concentrated. Azeotroping of the concentrate with tolueneyielded 3.8 g (90%) of4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-4-phosphatetracosan-1-aminium,4-oxide, hydroxide, inner salt as a solid, mp. 239°-242° (dec).

ANALYSIS: Calculated for C₂₄ H₅₂ NO₅ P.1.5H₂ O: 58.51%C; 11.25%H;2.84%N; 6.27%P. 58.25%C; 11.03%H; 2.67%N; 6.24%P.

EXAMPLE 84-Hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-4-phosphapentacosan-1-aminium,4-oxide, hydroxide, inner salt 1.25 hydrate Step 1

To a refluxing mixture of 1.26 g of magnesium turnings, 15.5 ml of1-chlorohexadecane, and 100 ml of anhydrous diethyl ether were added 0.5ml of a 3.2M solution of methylmagnesium bromide in diethyl ether and0.05 ml of ethyl bromide. The reaction mixture was refluxed for a periodof 6 hours. A solution of 3.0 g of4-[(tetrahydro-2H-pyran-2-yl)oxy]butanal in 10 ml of diethyl ether wasadded, and the reaction mixture refluxed for an additional hour. Thereaction mixture was poured into a mixture of ice and a saturatedaqueous solution of ammonium chloride, and filtered. Upon standing thefiltrate separated into organic and inorganic phases. The organic phasewas dried over anhydrous sodium sulfate and concentrated to an oil.Flash chromatography of the oil utilizing 25% diethyl ether/petroleumether yielded 4.8 g (70%) of1-[(tetrahydro-2H-pyran-2-yl)oxy]eicosan-4-ol as a solid, mp 39°-43°.

ANALYSIS: Calculated for C₂₅ H₅₀ O₃ : 75.32%C; 12.64%H. Found: 75.47%C;12.68%H.

Step 2

To a suspension of hexane washed sodium hydride (from 0.34 g of a 50%oil dispersion) in 5 ml of tetrahydrofuran was added a solution of 2.4 gof 1-[(tetrahydro-2H-pyran-2-yl) oxy]eicosan-4-ol (prepared as inStep 1) in 10 ml of tetrahydrofuran. Following the evolution ofhydrogen, 66 mg of tetrabutylammonium iodide and 0.83 ml of benzylbromide were added, and the reaction mixture was refluxed, undernitrogen, for three days. The reaction mixture was then diluted withwater. Upon standing the mixture formed aqueous and organic phases. Theaqueous phase was extracted with diethyl ether. The extract was thencombined with the organic phase and evaporated. The residue wasdissolved in diethyl ether, washed with water, dried over anhydroussodium sulfate and evaporated to give 3.0 g of an oil. The oil waspurified by means of flash chromatography utilizing as the eluent 5-10%ethyl ether/petroleum ether, to yield 2.2 g of4-benzyloxy-1-[(tetrahydro-2H-pyran-2-yl)oxy]eicosane as an oil.

The reaction was repeated on the same scale without tetrabutylammoniumiodide using dimethylformamide as the solvent and heating the mixture,under nitrogen, at 50° for 24 hours. Workup in a similar manner gave 2.5g of 4-benzyloxy-1-[(tetrahydro-2H-pyran-2-yl)oxy]eicosane as an oil.The combined products of both reactions were chromatographed by highpressure liquid chromatography utilizing 10% diethylether/dichloromethane as the eluent to yield 3.5 g (60%) of4-benzyloxy-1-[(tetrahydro-2H-pyran-2-yl)oxy]eicosane.

ANALYSIS: Calculated for C₃₂ H₅₆ O₃ : 78.63%C; 11.55%H. Found: 78.39%C;11.54%H.

Step 3

A solution of 11.5 g of4-benzyloxy-1-[(tetrahydro-2H-pyran-2-yl)oxy]eicosane (prepared asdescribed in Step 2) in 200 ml of ethanol was treated with 5 drops of 5Nhydrochloric acid and heated to 50° for 2 hours. The reaction mixturewas then neutralized with sodium bicarbonate and concentrated. Theconcentrate was extracted with diethyl ether. The extract was washedwith water and a saturated solution of sodium chloride, dried overanhydrous sodium sulfate and evaporated to give 9.7 g of an oil. The oilwas purified by means of high pressure liquid chromatography utilizingas an eluent 25% diethyl ether/petroleum ether to give 2.9 g (90%) of4-benzyloxyeicosan-1-ol as an oil.

ANALYSIS: Calculated for C₂₇ H₄₈ O₂ : 80.14%C; 11.96%H. Found: 80.23%C;12.22%H.

Step 4

To an anhydrous solution of 11.43 g of 4-benzyloxyeicosan-1-ol and 6.4ml of triethylamine in 300 ml of toluene was added, dropwise, undernitrogen, 4.02 g of 2-chloro-oxo-1,3,2-dioxaphospholane. The reactionmixture was stirred at ambient temperature overnight, filtered, andconcentrated to yield 15.65 g of an oil. The oil was dissolved in 150 mlof acetonitrile and added to a pressure reactor. Trimethylamine (26 g)was condensed into the reactor, under nitrogen, at a temperature of-40°. The reactor was then sealed and heated to 80° for 24 hours.Cooling the reaction mixture in an ice bath precipitated a solid. Thesolid was taken up in chloroform and concentrated. Flash chromatographyof the residue using as successive eluents chloroform/methanol (9:1 byvolume) followed by chloroform/methanol/water, (120:30:4 by volume),yielded 4.67 g (28%) of4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-4-phosphapentacosan-1-aminium-4-oxide,hydroxide inner salt 1.25 hydrate as a waxy solid.

ANALYSIS: Calculated for C₃₂ H₆₀ NO₅ P.1.25H₂ O: 64.88%C; 10.64%H;2.37%N; 5.23%P. Found: 64.52%C; 10.48%H; 2.39%H; 5.11%P.

EXAMPLE 94,9-Dihydroxy-N,N,N-trimethyl-3,5-dioxa-4-phosphopentacosan-1-aminium,4-oxide, hydroxide, inner salt monohydrate

A mixture of 3.3 g of4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-4-phosphapentacosan-1-aminium,4-oxide, hydroxide, inner salt 1.25 hydrate, 125 ml of ethanol and 0.4 gof 5% palladium on carbon was hydrogenated at 50 psi for 5 hours. Thereaction mixture was filtered, treated with 2 ml of water andconcentrated. Azeotroping with toluene yielded 2.55 g (92%) of4,9-dihydroxy-N,N,N-trimethyl-3,5-dioxa-4-phosphopentacosan-1-aminium,4-oxide, hydroxide, inner salt monohydrate, mp 240°-242°.

ANALYSIS: Calculated for C₂₅ H₅₄ NO₅ P.H₂ O: 60.33%C; 10.94%H; 2.815N;6.23%P. Found: 60.18%C; 11.17%H; 2.70%N; 6.14%P.

EXAMPLE 104-Hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-4-phosphahexacosan-1-aminium,4-oxide, hydroxide, inner salt monohydrate Step 1

To a 1M solution of allylmagnesium bromide in diethyl ether (15 ml) wasadded dropwise, a solution of 4.0 g of octadecanal in 20 ml oftetrahydrofuran. The reaction mixture was allowed to stand at roomtemperature for 16 hours. The reaction mixture was then poured into amixture of ice and water, acidified to a pH of 2 by the addition of a 5%aqueous solution of hydrochloric acid and concentrated. The concentratewas extracted with diethyl ether. The extract was washed with water,dilute aqueous solutions of sodium bicarbonate and sodium chloride,dried, and evaporated to yield an oil. Flash chromatography of the oilutilizing 10% diethyl ether/petroleum ether gave a wax. High pressureliquid chromatography of the wax utilizing 5% diethyl ether/petroleumether as the eluent yielded 2.8 g (61%) of 1-heneicosen-4-ol, mp48.0°-50.5°.

ANALYSIS: Calculated for C₂₁ H₄₂ O: 81.21%C; 13.63%H. Found: 81.28%C;13.88%H.

Step 2

To hexane washed sodium hydride (from 2.56 g of a 50% oil dispersion)was added dropwise, under nitrogen, a solution of 11.0 g of1-heneicosen-4-ol in 60 ml of dimethylformamide. The solution was heatedto 50° and 4.4 ml of benzyl bromide was added. The reaction mixture wasthen cooled to room temperature, combined with 300 ml of a water-icemixture, and extracted with hexane. The extract was dried over anhydrousmagnesium sulfate and concentrated, in vacuo, to a liquid. High pressureliquid chromatography of the liquid utilizing as an eluent 0.5% diethylether/hexane yielded 8.2 g (57%) of 4-benzyloxy-1-heneicosene.

ANALYSIS: Calculated for C₂₈ H₄₈ O: 83.93%C; 12.08%H. Found: 83.55%C;11.99%H.

Step 3

To a 33 ml solution of a 0.5M solution of 9-borabicyclo[3:3:1]nonane intetrahydrofuran was added dropwise, under nitrogen, a solution of 6.0 gof 4-benzyloxy-1-heneicosene in 30 ml of dry tetrahydrofuran. Afterstirring at room temperature for 3 hours, the reaction was quenched bysuccessive addition of 9 ml of ethanol, 3 ml of 6N sodium hydroxide and6.5 ml 30% hydrogen peroxide. The reaction mixture was heated at 50° for90 minutes and then allowed to stand at ambient temperature overnight.Upon standing, the reaction mixture separated into aqueous and organicphases. The aqueous phase was saturated with potassium carbonate, andthe organic phase was separated, washed with 15 ml of 10% solution ofsodium sulfite and 20 ml of saturated solution of sodium chloride, driedover potassium carbonate, and concentrated. The residue was taken up ina mixture of 20% diethyl ether/hexane, filtered and concentrated to anoil. Flash chromatography of the oil on silica gel using hexane/diethylether (2:1 by volume) as the eluent gave 4.88 g (78%) of4-benzyloxyheneicosan-1-ol.

ANALYSIS: Calculated for C₂₈ H₅₀ O₂ : 80.32%C; 12.09%H. Found: 79.82%C;12.21%H.

Step 4

To an anhydrous solution of 5 g of benzyloxyheneicosan-1-ol in 150 ml ofdry toluene was added dropwise, under nitrogen, 1.71 g of neat2-chloro-2-oxo-1,3,2-dioxaphospholane. The reaction mixture was stirredat ambient temperature overnight, filtered and concentrated. The residuewas dissolved in 100 ml of acetonitrile and added to a pressure reactor.Trimethylamine (9.22 g) was condensed into the pressure reactor, undernitrogen, at a temperature of -40° C. The reactor was then sealed andheated to a temperature of 70°-80° C. for 48 hours. Cooling the reactionmixture with ice precipitated a solid. The solid was taken up inchloroform and concentrated. Flash chromatography of the residue usingas successive eluents a mixture of chloroform/methanol (9:1 by volume),and chloroform/methanol/water (120:30:4 by volume) gave 1.18 g (19%) of4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-4-phosphahexacosan-1-aminium,4-oxide, hydroxide, inner salt monohydrate as a waxy solid.

ANALYSIS: Calculated for C₃₃ H₆₂ NO₅ P.sup.. H₂ O: 65.85%C; 10.71%H;2.33%N; 5.15%P. Found: 65.24%C; 10.66%H; 2.24%N; 5.19%P.

EXAMPLE 114-Hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-18-phenyl-4-phosphaoctadecan-1-aminium,4-oxide, hydroxide, inner salt trihydrate Step 1

A solution of 20 g of 11-phenyl-1-undecene in 600 ml of dry toluene wascooled to -45° C. Ozone was bubbled through the cooled solution at arate of 1.6 mmol/min for 49 minutes. The solution was warmed to roomtemperature, under nitrogen, and then transferred to a hydrogenationflask containing 1 g of 10% palladium-on-carbon and 200 g of 4Amolecular sieves. This mixture was hydrogenated for 3 hr at 50 psi,filtered and concentrated to give 18.26 g of 10-phenyldecanal.

Step 2

To a cooled solution of 1M allyl magnesium bromide in diethyl ether wasadded dropwise, under nitrogen, a solution of 18.2 g of 10-phenyldecanal(prepared as in Step 1) in 200 ml of dry tetrahydrofuran. The reactionmixture was stirred at about 5° for 15 minutes, at room temperature for1 hour, and then at reflux for 15 minutes. The reaction mixture wascooled to room temperature and poured into a mixture of 400 g of ice and40 ml of 9M sulfuric acid. Upon standing the mixture separated intoaqueous and organic layers. The organic layer was stirred for 15 minwith solid sodium bicarbonate and then concentrated. The aqueous layerwas extracted with diethyl ether (2×200 ml) and the extracts werecombined with the concentrated organic layer. The combined organics werewashed with water (300 ml) and a half-saturated aqueous solution ofsodium chloride (300 ml), dried over anhydrous magnesium sulfate,filtered and concentrated to an oil. High pressure liquid chromatographyof the oil using 10% diethyl ether/hexane as the eluent gave 6.98 g(30%) of 13-phenyl-1-tridecen-4-ol as an oil.

ANALYSIS: Calculated for C₁₉ H₃₀ O: 83.15%C; 11.02%H. Found: 82.79%C;11.23%H.

Step 3

To hexane-washed sodium hydride (from 0.92 g of a 50% oil dispersion)was added dropwise, under nitrogen, a solution of 4.06 g of13-phenyl-1-tridecen-4-ol in 50 ml of tetrahydrofuran. The solution washeated to 50° and 2.79 g of benzyl bromide was added, dropwise. Thereaction mixture was refluxed for 4 hours, quenched by the addition of10 ml of water, and concentrated. The residue was extracted withhexane/diethyl ether (2:1 by volume) (3×100 ml), washed with 300 ml ofwater and 300 ml of a saturated aqueous solution of sodium chloride, anddried over anhydrous magnesium sulfate. Concentration gave 5.51 g of anoil which was chromatographed by high pressure liquid chromatography toyield 3.09 g (58%) of 4-benzyloxy-13-phenyl-1-tridecene as an oil.

ANALYSIS: Calculated for C₂₆ H₃₆ O: 85.66%C; 9.95%H. Found: 85.44%C;9.95%H.

Step 4

To a 0.5M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (253ml) was added dropwise, under nitrogen, a solution of 41.8 g of4-benzyloxy-13-phenyl-1-tridecene in 100 ml of dry tetrahydrofuran. Themixture was stirred at room temperature for 3 hours, quenched by thesequential addition of 72 ml of ethanol, 24 ml of 6N solution of sodiumhydroxide, and 48 ml of a 30% solution of hydrogen peroxide. The mixturewas heated at 50° for 2.5 hours. Upon standing at room temperatureovernight, the mixture separated into aqueous and organic layers. Theorganic layer was washed with 100 ml of a 10% aqueous solution of sodiumsulfite and 100 ml of a saturated aqueous solution of sodium chloride,dried over anhydrous potassium carbonate and concentrated. Theconcentrate was taken up in 20% diethyl ether/hexane, filtered andconcentrated to an oil. The oil was purified by high pressure liquidchromatography using as an eluent hexane/diethyl ether (2:1 by volume)to give 32.7 g (75%) 4-benzyloxy-13-phenyl-tridecan-1-ol as an oil.

ANALYSIS: Calculated for C₂₆ H₃₈ O₂ : 81.62%C; 10.01%H. Found: 81.45%C;9.99%H.

Step 5

To a stirred solution of 12.6 g of 2-bromoethyl phosphorodichloridate in200 ml of diethyl ether cooled to 0° C., was added dropwise, in thefollowing order, 21 ml of pyridine, and a solution of 10 g of4-benzyloxy-13-phenyl-tridecan-1-ol in 200 ml of diethyl ether. Themixture was stirred at 0° for 30 min and warmed to room temperature.Water (100 ml) was then added and the mixture stirred at roomtemperature for 1 hour. The mixture was acidified to a pH of 2 by theaddition of 6N hydrochloric acid. Upon standing the mixture formedaqueous and organic layers. The organic layer was washed with 250 ml ofa saturated solution of sodium chloride, dried over anhydrous magnesiumsulfate, and concentrated. To a solution of 14 g of concentrate in 130ml of chloroform was added dropwise, in the following order, 210 ml ofacetonitrile, and 409 ml of a 33% aqueous solution of trimethylamine.The solution was heated at 60° for 20 hours, and concentrated. Theconcentrate was refluxed with 1000 ml of methanol and 10 grams of silvercarbonate for 2 hours, filtered, and concentrated. Flash chromatographyof the concentrate using as successive eluents chloroform:methanol (9.1by volume) and chloroform:methanol:water (120:30:4 by volume) gave 6.7 g(48%) of4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-18-phenyl-4-phosphaoctadecan-1-aminium,4-oxide, hydroxide, inner salt trihydrate as a gum.

ANALYSIS: Calculated for C₃₁ H₅₀ NOP.sup.. 3H₂ O: 61.87%C; 9.38%H;2.33%N; 5.15%P. Found: 61.84%C; 9.15%H; 2.295N; 5.33%P.

EXAMPLE 124,9-Dihydroxy-N,N,N-trimethyl-3,5-dioxa-18-phenyl-4-phosphaoctadecan-1-aminium,4-oxide, hydroxide, inner salt 2.5 hydrate

A mixture of 5.8 g of4-hydroxy-N,N,N-trimethyl-3,5-dioxa-18-phenyl-4-phosphaoctadecene-1-aminium,4-oxide, hydroxide, inner salt trihydrate, 218 ml of ethanol, 35 ml ofacetic acid and 0.8 g of 5% palladium-on-carbon was hydrogenated in aParr apparatus for 24 hours at 56 psi. The mixture was filtered,concentrated, and azeotroped with toluene to give an oil. The oil wasflash chromatographed using as successive eluents chloroform/methanol(9:1 by volume) and chloroform/methanol/water (120:30:4 by volume) togive 3.38 g (70%) of4,9-dihydroxy-N,N,N-trimethyl-3,5-dioxa-18-phenyl-4-phosphaoctadecan-1-aminium,4-oxide, hydroxide, inner salt 2.5 hydrate as a waxy solid, mp220°-223°.

ANALYSIS: Calculated for C₂₄ H₄₄ NO₅ P.sup.. 2.5H₂ O: 57.35%C; 7.83%H;2.78%H; 6.16%P. Found: 56.9%C; 9.51%H; 2.99%N; 6.16%P.

EXAMPLE 134-Hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-18-phenoxy-4-phosphaoctadecan-1-aminium,4-oxide, hydroxide, inner salt monohydrate Step 1

Ozone was bubbled through a solution of 20 g of 11-phenoxy-1-undecene in600 ml of anhydrous toluene cooled to -45° at a rate of 1.6 mmol/min for49 min. The solution was warmed to room temperature and then transferredto a hydrogenation flask containing 1 g of 10% palladium on carbon and200 g of 4A molecular sieves. The mixture was hydrogenated at 50 psi for2 hours, filtered and concentrated to give 20.1 g of 10-phenoxydecanal.

Step 2

To 85 ml of a 1M solution of allyl magnesium bromide in diethyl ethercooled in ice bath was added dropwise, under nitrogen, a solution of 20g of 10-phenoxydecanal in 200 ml of dry tetrahydrofuran. The mixture waspoured into 400 ml of ice and 30 ml of 9M sulfuric acid was added. Uponstanding the mixture formed aqueous and organic layers. The organiclayer was stirred for 15 min with solid sodium bicarbonate andconcentrated. The aqueous layer was extracted with diethyl ether (2×200ml) and the extracts were combined with the concentrated organic layer.The combined organics were washed with 300 ml of water and 300 ml of ahalf-saturated aqueous solution of sodium chloride, filtered, andconcentrated. The residue was flash chromatographed utilizing assuccessive eluents 5% diethyl ether/hexane, 10% diethyl ether/hexane,and 25% diethyl ether/hexane to give 18.51 g (42%) of13-phenoxy-1-tridecen-4-ol as a solid, m.p. 50°-52°.

ANALYSIS: Calculated for C₁₉ H₃₀ O₂ : 78.57%C; 10.41%H. Found: 78.61%C;10.38%H.

Step 2

To hexane-washed sodium hydride (from 1.39 g of a 50% oil dispersion)was added dropwise, under nitrogen, a solution of 6.46 g of13-phenoxy-1-tridecen-4-ol in 25 ml of dry tetrahydrofuran. The solutionwas warmed to 50° C. and a solution of 2.91 ml of benzyl bromide in 25ml of dimethylformamide was added. The mixture was refluxed for 4 hours,cooled to room temperature, and quenched with 10 ml of water, andconcentrated. The concentrate was extracted with hexane/diethyl ether(2:1 by volume) (3×100 ml). The combined extracts were washed with water(200 ml) and a saturated aqueous solution of sodium chloride (200 ml),dried over anhydrous magnesium sulfate and concentrated to an oil. Theoil was chromatographed by high pressure liquid chromatography usingdiethyl ether:hexane (1:49 by volume) to give 6.34 g (75%) of4-benzyloxy-13-phenoxy-1-tridecene.

ANALYSIS: Calculated for C₂₆ H₂₆ O₂ : 82.05%C; 9.59%H. Found: 82.08%C;9.53%H.

Step 3

To 388 ml of a 0.5M solution of 9-borabicyclo[3.3.1]nonane intetrahydrofuran was added dropwise, under nitrogen, a solution of 66.3 gof 4-benzyloxy-13-phenoxy-1-tridecene in 100 ml of tetrahydrofuran. Thesolution was stirred for 3 hours, then quenched by the sequentialaddition of 98 ml of ethanol, 34 ml of a 6N solution of sodium hydroxideand 70 ml of 30% hydrogen peroxide. The mixture was heated at 50° C. for3 hours and then allowed to stand at room temperature overnight. Uponstanding the mixture formed aqueous and organic layers. The organiclayer was washed with 100 ml each of a 10% aqueous solution of sodiumsulfite and a saturated aqueous solution of sodium chloride, dried overanhydrous potassium carbonate and concentrated. The residue was taken upin a mixture of diethyl ether:hexane (1:4), filtered, and concentratedto give 68.35 g of an oil. High pressure liquid chromatography of 24 gof the oil using as an eluent hexane/diethyl ether (2:1 by volume) gave19.02 g (77%) of 4-benzyloxy-13-phenoxy-tridecan-1-ol as an oil.

Step 4

To a solution of 6.5 g of 4-benzyloxy-13-phenoxytridecan-1-ol in 60 mlof carbon tetrachloride was added dropwise, in the following order, 4.7g of 2-bromoethyl phosphodichloridate and 2.7 ml of triethylamine. Themixture was stirred at room temperature for 2.5 hours, filtered, andconcentrated. The residue was taken up in 60 ml of tetrahydrofuran, and60 ml of a 0.5M sodium acetate was added. The mixture was stirred atroom temperature for 60 hours, quenched by the addition of 20 ml of a 5%aqueous solution of hydrochloric acid and 30 ml of a saturated aqueoussolution of sodium chloride, and extracted with ethyl acetate (3×100ml). The combined extracts were dried over anhydrous magnesium sulfateand concentrated. Flash chromatography of the concentrate using 5%methanol/chloroform as the eluent gave 3.4 g (30%) of 2-bromoethyl(4-benzyloxy-13-phenoxytridecan-1-yl)phosphate.

A solution of 2-bromoethyl(4-benzyloxy-13-phenoxytridecan-1-yl)phosphate (3.21 g) in 23.2 ml ofchloroform, 37.5 ml of isopropanol, 37.5 ml of acetonitrile and 72.7 mlof a 33% aqueous solution of trimethylamine was stirred at 50° for 20hours. The mixture was concentrated, and the concentrate purified byflash chromatography using as successive eluents chloroform/methanol(9:1 by volume) and chloroform/methanol/5% aqueous ammonium hydroxide(13:7:1 by volume) to give 3.14 g of the hydrobromide. The hydrobromidewas taken up in 50 ml of methanol and 1.5 g of silver carbonate wasadded. The mixture was refluxed for 2 hours, filtered and concentratedto a gum. Flash chromatography of the gum using as successive eluentschloroform/methanol (9:1 by volume) and chloroform/methanol/water(65:25:4 by volume) gave 2.08 g of4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-18-phenoxy-4-phosphaoctadecan-1-aminium,4-oxide, hydroxide, inner salt monohydrate as a solid, m.p. 173°-175°.

ANALYSIS: Calculated for C₃₁ H₅₀ NO₆ P.H₂ O: 64.00%C; 8.70%H; 2.41%N;5.32%P. Found: 63.70%C; 8.93%H; 2.34%N; 5.33%P.

EXAMPLE 144,9-Dihydroxy-N,N,N-trimethyl-3,5-dioxa-18-phenoxy-4-phosphaoctadecan-1-aminium,4-oxide, hydroxide, inner salt dihydrate

A mixture of 12 g of4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-18-phenyoxy-4-phosphaoctadecan-1-aminium,4-oxide, hydroxide, inner salt monohydrate, 150 ml of ethanol, 50 ml ofacetic acid and 1.5 g of 5% palladium on carbon was hydrogenated for 20hours at 56 psi, filtered and concentrated. Flash chromatography of theresidue using as successive eluents chloroform/methanol (9:1 by volume)and chloroform/methanol/water (120:30:4 by volume) gave 7.9 g (74%) of4,9-dihydroxy-N,N,N-trimethyl-3,5-dioxa-18-phenoxy-4-phosphaoctadecan-1-aminium,4-oxide, hydroxide, inner salt dihydrate as a solid.

ANALYSIS: Calculated for C₂₄ H₄₄ NO₆ P.2H₂ O: 56.56%C; 9.49%H; 2.74%N;6.07%P. Found: 56.48%C; 9.14%H; 2.91%N; 6.14%P. ##STR16##

What is claimed is:
 1. A compound of the formulawherein R¹ is selected from the group consisting of hydrogen, ##STR17## wherein a is an integer having a value of 0 to 2, inclusive, X is selected from the group consisting of alkyl radicals having 1 to 6 carbon atoms, inclusive, alkoxy radicals having 1 to 6 carbon atoms, inclusive, halogen, hydroxy and trifluoromethyl radicals, b is an integer having a value from 0 to 2, inclusive, and Y is selected from the group consisting of alkyl radicals having 1 to 6 carbon atoms, inclusive, alkoxy radicals having 1 to 6 carbon atoms, inclusive, halogen, hydroxy and trifluoromethyl radicals; R² is selected from the group consisting of hydrogen, alkyl radicals having up to 6 carbon atoms inclusive, and ##STR18## wherein c is an integer having a value of 0 to 1 and Z is an alkoxy radical having 1 to 6 carbon atoms; R³ is ##STR19## wherein R⁴ is an alkyl radical having up to 6 carbon atoms, inclusive, R⁵ and R₆ are independently alkyl radicals having up to 6 carbon atoms, inclusive, or, taken together with the nitrogen atom to which they are attached form a group of the formula ##STR20## wherein r is 0 or 1; A is a bivalent radical of the formula --C_(n) H_(2n) -- wherein n is an integer having a value from 1 to 20, inclusive, and m is an integer having a value of 3 or 4; and A¹ is a bivalent radical of the formula --C_(p) H_(2p) wherein p is an integer having a value from 2 to 10, inclusive, with the proviso that the sum of n and p does not exceed 25; the geometrical isomers, or optical antipodes thereof.
 2. A compound of the formula: ##STR21## wherein R¹ is selected from the group consisting of hydrogen, ##STR22## wherein a is an integer having a value of 0 to 2, inclusive, X is selected from the group consisting of alkyl radicals having 1 to 6 carbon atoms, inclusive, alkoxy radicals having 1 to 6 carbon atoms, inclusive, halogen, hydroxy and trifluoromethyl radicals, b is an integer having a value from 0 to 2, inclusive, and Y is selected from the group consisting of alkyl radicals having 1 to 6 carbon atoms, inclusive, alkoxy radicals having 1 to 6 carbon atoms, inclusive, halogen, hydroxy and trifluoromethyl radicals; R² is selected from the group consisting of hydrogen, alkyl radicals having up to 6 carbon atoms inclusive, and ##STR23## wherein c is an integer having a value of 0 or 1 and Z is an alkoxy radical having 1 to 6 carbon atoms; R³ is ##STR24## wherein R⁴ is an alkyl radical having up to 6 carbon atoms, inclusive, and R⁵ and R⁶ are independently alkyl radicals having up to 6 carbon atoms, inclusive, or, taken together with the nitrogen atom to which they are attached form a group of the formula ##STR25## wherein r is 0 or 1; x is an integer having a value from 1 to 20 inclusive; and y is an integer having a value from 2 to 5 inclusive; and the geometrical isomers or optical antipodes thereof.
 3. A compound according to claim 2 wherein R¹ is hydrogen.
 4. A compound according to claim 3 wherein R² is hydrogen.
 5. A compound according to claim 4 wherein R³ is ##STR26## wherein R⁴, R⁵ and R⁶ are independently alkyl radicals having up to 6 carbon atoms inclusive.
 6. The compound of claim 5 which is 4,9-dihydroxy-N,N,N-trimethyl-3,5-dioxa-4-phosphaoctadecan-1-aminium, 4-oxide, hydroxide, inner salt.
 7. The compound of claim 5 which is 4,9-dihydroxy-N,N,N-trimethyl-3,5-dioxa-4-phosphatetracosan-1-aminium, 4-oxide, hydroxide, inner salt.
 8. The compound of claim 5 which is 4,9-dihydroxy-N,N,N-trimethyl-3,5-dioxa-4-phosphapentacosan-1-aminium, 4-oxide, hydroxide, inner salt.
 9. A compound according to claim 1 wherein R¹ is hydrogen; and R² is ##STR27## wherein c is an integer having a value of 0 or 1 inclusive; Z is an alkoxy radical having 1 to 6 carbon atoms.
 10. A compound according to claim 9 wherein R³ is ##STR28## wherein R⁴, R⁵ and R⁶ are independently alkyl radicals having up to 6 carbon atoms, inclusive.
 11. The compound of claim 10 which is 4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-4-phosphaoctadecan-1-aminium, 4-oxide, hydroxide, inner salt.
 12. The compound of claim 10 which is 4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-4-phosphatetracosan-1-aminium, 4-oxide, hydroxide, inner salt.
 13. The compound of claim 10 which is 4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-4-phosphahexacosan-1-aminium, 4-oxide, hydroxide, inner salt.
 14. The compound of claim 10 which is 4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-4-phosphapentacosan-1-aminium, 4-oxide, hydroxide, inner salt.
 15. A compound according to claim 2 wherein R¹ is hydrogen, R² is ##STR29## wherein c is an integer having a value of 0 or 1; Z is an alkoxy radical having 1 to 6 carbon atoms, inclusive; and R³ is ##STR30## wherein R⁴ is an alkyl radical having up to 6 carbon atoms, inclusive and R⁵ and R⁶ together with the nitrogen atom to which they are attached form a group of the formula ##STR31## wherein r is 0 or
 1. 16. The compound of claim 15 which is 4-hydroxy-N-methyl-3,5-dioxa-9-phenylmethoxy-4-phosphaoctadecan-1-pyrrolidinium, 4-oxide, hydroxide, inner salt.
 17. The compound of claim 15 which is 4-hydroxy-N-methyl-3,5-dioxa-9-phenylmethoxy-4-phosphatetracosan-1-pyrrolidinium, 4-oxide, hydroxide, inner salt.
 18. A compound of claim 1 wherein R¹ is hydrogen, R² is hydrogen, and R³ is ##STR32## wherein R⁴ is an alkyl radical having up to 6 carbon atoms, inclusive and R⁵ and R⁶ together with the nitrogen atom to which they are attached form a group of the formula ##STR33## wherein r is 0 or
 1. 19. The compound of claim 18 which is 4,9-dihydroxy-N-methyl-3,5-dioxa-4-phosphatetracosan-1-pyrrolidinium, 4-oxide, hydroxide, inner salt.
 20. A compound according to claim 1 wherein R¹ is ##STR34## wherein a is an integer having a value from 0 to 2, inclusive, and X is selected from the group consisting of alkyl radicals having 1 to 6 carbon atoms, inclusive, alkoxy radicals having 1 to 6 carbon atoms inclusive, halogen, hydroxy and trifluoromethyl radicals.
 21. A compound according to claim 20 wherein R² is hydrogen.
 22. A compound according to claim 21 wherein R³ is ##STR35## wherein R⁴, R⁵ and R⁶ are independently alkyl radicals having up to 6 carbon atoms, inclusive.
 23. The compound of claim 22 which is 4,9-dihydroxy-N,N,N-trimethyl-3,5-dioxa-18-phenyl-4-phosphaoctatadecan-1-aminium, 4-oxide, hydroxide, inner salt.
 24. A compound according to claim 1 wherein R¹ is ##STR36## wherein a is an integer having a value of 0 to 2, inclusive, and X is selected from the group consisting of alkyl radicals having 1 to 6 carbon atoms, inclusive, alkoxy radicals having 1 to 6 carbon atoms, inclusive, halogen, hydroxy and trifluoromethyl radicals; R² is ##STR37## wherein c is an integer having a value of 0 or 1; Z is an alkoxy radical having 1 to 6 carbon atoms; and R³ is ##STR38## wherein R⁴, R⁵ and R⁶ are independently alkyl radicals having up to 6 carbon atoms, inclusive.
 25. The compound of claim 24 which is 4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-18-phenyl-4-phosphaoctadecan-1-aminium, 4-oxide, hydroxide, inner salt.
 26. A compound according to claim 1 wherein R¹ is ##STR39## wherein b is an integer having a value from 0 to 2 inclusive, and Y is selected from the group consisting of alkyl radicals having 1 to 6 carbon atoms; alkoxy radicals having 1 to 6 carbon atoms, halogen, hydroxy and trifluoromethyl radicals.
 27. A compound according to claim 26 wherein R² is hydrogen.
 28. A compound according to claim 27 wherein R³ is ##STR40## wherein R⁴, R⁵ and R⁶ are independently alkyl radicals having up to 6 carbon atoms, inclusive.
 29. A compound according to claim 2 wherein R¹ is ##STR41## wherein b is an integer having a value from 0 to 2 inclusive, and Y is selected from the group consisting of alkyl radicals having 1 to 6 carbon atoms, inclusive; alkoxy radicals having 1 to 6 carbon atoms, inclusive, halogen, hydroxy and trifluoromethyl radicals; R² is hydrogen, and R³ is ##STR42## wherein R⁴, R⁵ and R⁶ are independently alkyl radicals having up to 6 carbon atoms, inclusive.
 30. The compound of claim 29 which is 4,9-dihydroxy-N,N,N-trimethyl-3,5-dioxa-18-phenoxy-4-phosphaoctadecan-1-aminium, 4-oxide, hydroxide, inner salt.
 31. A compound according to claim 2 wherein R¹ is ##STR43## wherein a is an integer having a value from 0 to 2, inclusive, and X is selected from the group consisting of alkyl radicals having 1 to 6 carbon atoms, inclusive; alkoxy radicals having 1 to 6 carbon atoms, inclusive, halogen, hydroxy and trifluoromethyl radicals; R² is ##STR44## wherein c is an integer having a value of 0 or 1; Z is an alkoxy radical having 1 to 6 carbon atoms and; R³ is ##STR45## wherein R⁴, R⁵ and R⁶ are independently alkyl radicals having up to 6 carbon atoms, inclusive.
 32. The compound of claim 31 which is 4-hydroxy-N,N,N-trimethyl-9-phenylmethoxy-3,5-dioxa-18-phenyl-4-phosphaoctadecan-1-aminium, 4-oxide, hydroxide, inner salt.
 33. A compound according to claim 2 wherein R² is hydrogen or ##STR46## wherein c is an integer having a value from 0 to 2, inclusive, and Z is selected from the group consisting of alkyl radicals having 1 to 6 carbon atoms, inclusive, halogen, hydroxy and trifluoromethyl radicals.
 34. A compound according to claim 3 wherein R³ is ##STR47## wherein R⁴ is an alkyl radical having up to 6 carbon atoms, inclusive, and R⁵ and R⁶ together with the nitrogen atom to which they are attached form a group of the formula ##STR48## wherein r is 0 or
 1. 35. A compound according to claim 3 wherein R³ is ##STR49## wherein R⁴, R⁵ and R⁶ are independently alkyl radicals having up to 6 carbon atoms, inclusive. 